1. Field of the Invention
This invention relates to devices and methods for the non-invasive determination of concentrations of analytes in a human subject in vivo and to methods of improving calibration of these devices and methods.
2. Discussion of the Art
Non-invasive monitoring of concentrations of analytes in the human body by means of optical devices and optical methods is an important tool for clinical diagnosis. xe2x80x9cNon-invasivexe2x80x9d (alternatively referred to herein as xe2x80x9cNIxe2x80x9d) monitoring techniques measure in vivo concentrations of analytes in the blood or in the tissue without the need for obtaining a blood sample from the human body. As used herein, a xe2x80x9cnon-invasivexe2x80x9d technique is one that can be used without removing a sample from, or without inserting any instrumentation into, the human body. The ability to determine the concentration of an analyte, or a disease state, in a human subject without performing an invasive procedure, such as removing a sample of blood or a biopsy specimen, has several advantages. These advantages include ease in performing the test, reduced pain and discomfort to the patient, and decreased exposure to potential biohazards. These advantages tend to promote increased frequency of testing, accurate monitoring and control of a disease condition, and improved patient care. A well-known non-invasive optical technique is pulse oximetry. Oxygenation of blood in the tissue and cerebral oxygen saturation can be measured by this technique, and the measurements can be used for clinical applications. Non-invasive determination of the hemoglobin concentration and the hematocrit value have the potential to be applied for diagnosis of anemia in infants and mothers, for localizing tumors, and for diagnosis of hematoma and internal bleeding.
Non-invasive diagnosis and monitoring of diabetes may be the most important non-invasive diagnostic procedure. Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism characterized by an absolute or relative insulin deficiency, hyperglycemia, and glycosuria. At least two major variants of the disease have been identified. xe2x80x9cType Ixe2x80x9d accounts for about 10% of diabetics and is characterized by a severe insulin deficiency resulting from a loss of insulin-secreting beta cells in the pancreas. The remainder of diabetic patients suffer from xe2x80x9cType IIxe2x80x9d, which is characterized by an impaired insulin response in the peripheral tissues (Robbins, S. L. et al., Pathologic Basis of Disease, 3rd Edition, W. B. Saunders Company, Philadelphia, 1984, p. 972). If uncontrolled, diabetes can result in a variety of adverse clinical manifestations, including retinopathy, atherosclerosis, microangiopathy, nephropathy, and neuropathy. In its advanced stages, diabetes can cause blindness, coma, and ultimately death.
Tight control of blood glucose level in the xe2x80x9cnormal rangexe2x80x9d, 60-120 mg/dL, is necessary for diabetics to avoid or reduce complications resulting from hypoglycemia and hyperglycemia. To achieve this level of control, diabetics should test their blood glucose level several times per day. Thus, there is a need for accurate and frequent, preferably continuous, glucose monitoring to reduce the effects of diabetes.
U.S. Pat. Nos. 5,086,229; 5,324,979; and 5,237,178 describe non-invasive methods for measuring blood glucose level involving radiation in the near infrared region of the electromagnetic spectrum (600 nm to 1200 nm). In these methods, a blood-containing body part (e.g., a finger) is illuminated by one or more light sources, and one or more detectors detect the light transmitted through the body part. A glucose level is derived from a comparison to reference spectra for glucose and background interferants.
U.S. Pat. Nos. 5,362,966; 5,237,178; 5,533,509; and 4,655,225 describe the use of radiation in the near infrared range of the electromagnetic spectrum, that is, from 1200 nm to about 3000, for the optical measurement of blood glucose level. The principles of operation are similar to those described for measurements employing radiation in the 600 nm to 1200 nm range, except that the light penetration depth in this wavelength range is less than that in the 600 nm to 1200 nm wavelength range. As a consequence, most optical measurements in this region of the electromagnetic spectrum use an arrangement based on reflectance measurement rather than transmittance measurement. U.S. Pat. Nos. 5,313,941; 5,115,133; 5,481,113; 5,452,716; 5,515,847; 5,348,003; and DE 4242083 describe optical measurements in the infrared region of the electromagnetic spectrum employing radiation in the range of from about 3000 nm to about 25000 nm.
These glucose determination methods of the prior art are silent as to the effect of temperature at the measurement site on the optical signal. They are also silent as to the effect of temperature on the propagation of light in tissue and to the effect of modulating the temperature between preset limits during the optical measurement. U.S. Pat. Nos. 3,628,525; 4,259,963; 4,432,365; 4,890,619; 4,926,867; 5,131,391; and European Patent Application EP 0472216 describe oximetry probes having heating elements designed to be placed against a body part. U.S. Pat. No. 5,148,082 describes a method for increasing the blood flow in a patient""s tissue during a photoplethysmography measurement by heating the tissue with a semiconductor device mounted in a sensor.
Spatially resolved diffuse reflectance techniques have been described U.S. Pat. Nos. 5,551,422; 5,676,143; 5,492,118; 5,057,695, European Patent Application EP 0810429. In these techniques, light is introduced into a sample and the intensity of the light re-emitted from the sample is measured at several distances from the site at which light is introduced into the sample. U.S. Pat. Nos. 5,187,672; 5,122,974; 5,492,769 and 5,492,118 describe frequency-domain reflectance measurements, which use optical systems similar to those used for spatially resolved diffuse reflectance measurements, except that the light source and the detector are modulated at a high frequency.
A major assumption for using these techniques is that tissue can be represented as an infinite-homogeneous slab. These techniques ignore the nature of skin, which is a layered structure. Further, these techniques ignore the effect of the temperature of the skin on propagation of light in cutaneous layers. U.S. Pat. No. 5,551,422 describes a glucose sensor utilizing spatially resolved diffuse reflectance techniques, wherein the sensor is brought to a specified temperature, preferably somewhat above normal body-temperature, with a thermostatically controlled heating system.
The light penetration depth in tissue depends on wavelength of the illuminating light. Generally, light in the near infrared region of the electromagnetic spectrum penetrates deeper into the tissue at longer wavelengths within the therapeutic window (600 nm to 1300 nm). Temperature affects the light penetration depth in tissue. Light at a given wavelength will penetrate deeper into a tissue, such as skin, as temperature of the tissue is lowered.
When human skin is illuminated by light of a single wavelength and the temperature of the skin is uncontrolled, the light penetration depth will vary from person to person, depending on the temperature of the subject""s skin. When the skin is illuminated at a plurality of wavelengths and the temperature of the skin is not controlled, there will be even greater variation in light penetration depth. The ultimate result will be an erroneous estimate of optical parameters, and consequently, an erroneous determination of the concentration of an analyte in vivo.
U.S. application Ser. No. 09/080,470, filed May 18, 1998, assigned to the assignee of this application, and WO 99/59464 describe a non-invasive glucose sensor employing a means for controlling the temperature of a sample. One purpose of controlling the temperature of the skin during the optical measurement is to minimize the effect of physiological variables.
Although a variety of detection techniques have been disclosed in the art, there is still no commercially available non-invasive device that provides measurements of the concentrations of analytes with an accuracy that is comparable to that of measurements made by current commercially available invasive methods. Non-invasive measurements obtained by methods of the prior art are based on the assumption that the tissue, e.g., skin, comprises a single uniform layer that has a single uniform temperature. As a result, current approaches to non-invasive metabolite testing, such as monitoring of blood glucose level, hemoglobin determination or hematocrit monitoring, have not achieved acceptable precision and accuracy.
Thus, there is a need for improved devices and methods for non-invasive testing and quantification of analytes in the human body. It is desired that these methods and devices not be adversely affected by variations in temperature of the skin and that they account for the effects of the various optical properties of skin and the effect of temperature on the optical properties of the various layers of the skin.
This invention provides a method for the determination of concentrations of analytes, e.g., glucose, and other metabolites in human tissue, wherein the temperature of a defined cutaneous volume of tissue, e.g., human skin, is controlled. The method involves calculating the concentration of an analyte in the tissue by taking into consideration the values of optical parameters of a sample of tissue measured in the defined cutaneous volume of the tissue at various temperatures. The selection of the defined volume is a function of the sampling distance along the surface of the tissue, the wavelength of light used to illuminate the tissue, and the temperature in the defined volume of tissue, which is a function of the temperature at the surface of the tissue.
In one embodiment of the method of this invention, an optical signal re-emitted from a defined cutaneous volume of the tissue is measured, as the temperature of this volume is maintained at a constant value. In another embodiment of the method of this invention, the temperature of the defined cutaneous volume of the tissue is varied within a defined physiological range to change the depth of penetration of light into the tissue, thereby achieving a depth profile for the optical signal.
The method of this invention is useful for monitoring the concentrations of analytes in tissues, testing at the point of care, and screening for diseases, such as, for example, diabetes. The method of this invention utilizes changes in temperature and selection of wavelengths to define cutaneous volumes below the surface of the tissue, in which volumes the concentration of an analyte can be determined.
In one aspect, this invention provides a method for establishing a calibration relationship to determine the concentration of an analyte or a disease state in a biological tissue. The method comprises the steps of:
(a) selecting a sampling area on the surface of a biological tissue;
(b) setting the temperature of the sampling area of the biological tissue to a first temperature;
(c) introducing light at a light introduction site, the light introduction site being within the sampling area and collecting light re-emitted at a light collection site, the light collection site being within the sampling area, the light introduction site and the light collection site being separated by a sampling distance, the introduced light being within a first wavelength range;
(d) performing at least one optical measurement at the sampling distance;
(e) setting the temperature of the sampling area of the biological tissue to a second temperature, the second temperature being different from the first temperature;
(f) repeating steps (c) and (d) at the second temperature, the introduced light at the second temperature being within a second wavelength range;
(g) determining the value of at least one optical parameter at the first temperature and at at least one wavelength within the first wavelength range and the value of the at least one optical parameter at the second temperature and at at least one wavelength within the second wavelength range; and
(h) establishing a mathematical relationship that relates the value of the at least one optical parameter at the first temperature and at the at least one wavelength within the first wavelength range and the value of the at least one optical parameter at the second temperature and at the at least one wavelength within the second wavelength range with an independently measured concentration of the analyte or an independent measurement of the disease state.
The aforementioned calibration relationship can be used to determine the concentration of an analyte or a disease state by means of a subsequent determination of at least one optical parameter at at least one wavelength and at least one temperature. In a preferred embodiment of this invention, at least one parameter can be selected from the group consisting of reflectance of the tissue, attenuation coefficient of the tissue, absorption coefficient of the tissue, scattering coefficient of the tissue, and depth of penetration of light in the tissue.
The temperatures at which the surface of the skin is maintained lie within a physiological temperature range, namely, from about 10xc2x0 C. to about 45xc2x0 C. Preferably, temperatures are selected so as to assure comfort during the measurements. Accordingly, a preferred temperature range is from about 15xc2x0 C. to about 42xc2x0 C., and a more preferred temperature range is from about 20xc2x0 C. to about 40xc2x0 C.
The light used in the method of this invention can have wavelengths ranging from about 400 nm to about 2000 nm, preferably ranging from about 500 nm to about 1800 nm. It is possible to select a range of wavelengths that allows the use of one type of detector. Thus, a wavelength range of from about 400 nm to about 1100 nm can be used with an inexpensive silicon photodiode detector, and a wavelength range of from about 700 nm to about 1900 nm can be used with an Indium/gallium arsenide detector. Preferably, the light introduced into the biological tissue has at least four wavelengths, at least two of the wavelengths being from about 500 nm to about 800 nm, and at least two of the wavelengths being from about 800 nm to about 1100 nm. Hybrid detectors having wider wavelength ranges can be used to detect light having wavelengths in all or most of the visible and near infrared regions of the electromagnetic spectrum.
The optical measurements for the method of this invention can be performed at a single sampling distance and at a plurality of wavelengths. This sampling distance defines the average depth in the sample at which the majority of the re-emitted light is collected and detected. The selection of the wavelengths and temperature further define the cutaneous volume from which the majority of the re-emitted light signal is scattered.
The volume of tissue subjected to temperature control and optical examination ranges from about 0.1 cubic millimeter to about 10 cubic millimeters, preferably from about 0.2 cubic millimeter to about 5 cubic millimeters, more preferably from about 0.2 cubic millimeter to about 2 cubic millimeters.
The method of this invention provides several advantages over methods and apparatus of the prior art used for the non-invasive determination of glucose and other analytes in the human body. Performing the optical signal measured at a single sampling distance eliminates the need for a plurality of light collection sites, the use of multiple detectors or multiple fibers. A single sampling distance leads to simpler, more robust optical instruments that are easier to calibrate and to maintain.
The method of this invention does not rely on calculating optical parameters that depend on the diffusion theory approximation or Monte Carlo simulations. Thus the calibration parameters obtained are independent of the assumptions that are usually used when applying the diffusion theory approximation or the Monte Carlo simulations.
Further, the method of temperature modulation of this invention can be used with prior art spatially resolved diffuse reflectance measurements to improve the correlation parameters, such as the correlation coefficient and the standard error of calibration, in meal-tolerance test or glucose tolerance test calibration procedures.
The method of this invention overcomes the shortcomings of the spatially resolved diffuse reflectance methods of the prior art by:
a) using a small measurement volume, in order to detect signal from an average depth of 1 to 3 mm in the tissue, thus avoiding adipose tissue and deep tissue structures;
b) allowing the monitoring of different depth in tissue, within a maximum depth of 3 mm;
c) offering simplified instrumentation that does not require illumination or collection of light at a plurality of positions;
d) allowing control and modulation of temperature in the shallow depth in tissue from where the optical signal is collected.
The method of this invention offers a novel use of combining temperatures and wavelengths to define a specific volume in tissue from which the signal to be measured is re-emitted, thereby improving the precision of the measurement.